OBJECTIVE--The objectives of the study were to determine whether the cell cycle transcription factor, FoxM1, is required for glucose homeostasis and Î²-cell mass expansion in maternal islets during pregnancy and whether FoxM1 is essential for placental lactogen (PL)-induced Î²-cell proliferation. RESEARCH DESIGN AND METHODS--Î²-Cell mass, Î²-cell proliferation, and glucose homeostasis were assessed in virgin, pregnant, and postpartum mice with a pancreas-wide Foxm1 deletion (FoxM1[sup â–³panc]). Wild-type islets were cultured with or without PL and examined for Foxm1 induction. Transgenic mice overexpressing PL in Î²-cells were bred with FoxM1[sup â–³panc] mice, and Î²-cell proliferation was examined. RESULTS--Foxm1 was upregulated in maternal islets during pregnancy. In contrast to controls, Î²-cell proliferation did not increase in pregnant FoxM1[sup â–³panc] females. Mutant islets showed increased Menin and nuclear p27. FoxM1[sup â–³panc] females developed gestational diabetes mellitus as pregnancy progressed. After parturition, euglycemia was restored in FoxM1[sup â–³panc] females, but islet size was significantly reduced. Strikingly, Î²-cell mass was normal in postpartum FoxM1[sup â–³panc] pancreata due to a combination of increased Î²-cell size and islet neogenesis. Evidence for neogenesis included increased number of endocrine clusters, increased proportion of smaller islets, and increased neurogenin 3 or insulin expression in cells adjacent to ducts. PL induced Foxm1 expression in cultured islets, and FoxM1 was essential for PL-mediated increases in Î²-cell proliferation in vivo. CONCLUSIONS--FoxM1 is essential for Î²-cell compensation during pregnancy. In the absence of increased Î²-cell proliferation, neogenesis is induced in postpartum FoxM1[sup â–³panc] pancreata. Our results suggest that FoxM1 functions downstream of PL to mediate its effects on Î²-cell proliferation. Diabetes 59:143-152, 2010

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